# Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $336,875

## Abstract

Although medical recommendations about diet are made for cardiovascular disease and diabetes, this is not
the case for most pain disorders. However, diet could be a risk factor for chronic pain conditions as linoleic
(LA) and arachidonic (AA) acid are essential omega-6 polyunsaturated fatty acids (ω-6 PUFA), where their cell
membrane levels are regulated by dietary intake. Importantly, the oxidized metabolites of LA or AA have potent
biological actions in activating targets such as transient receptor potential (TRP) channels, which are
expressed on primary afferent nociceptors. Thus, the incorporation and release of omega-6 PUFAs from
cellular membranes plays a key role in regulating nociceptor activities, including pain. Our central hypothesis is
that dietary omega-6 PUFA-induced increase in nociceptor activities is mediated by the activity of PLA2
subtypes, resulting in activation of neuronal receptors/channels. This is supported by mulitple lines of
preliminary data using a robust set of behavioral, electrophysiologic, imaging, and RNAseq methodologies.
Aim 1. Determine which subclasses of DRG afferents mediate HFD-induced nociception. We will use six
Cre+/--DTA+/- mouse lines generated for the conditional ablation of neurons expressing Nav1.8 (all
nociceptors), TrpV1 (nociceptors), CGRP (peptidergic nociceptors), Mrgprd (non-peptidergic nociceptors),
TrkC (Aβ low threshold mechanoreceptors (LTMR)) and TrkB (Aδ LTMR fibers) (Table 1). Mice will be fed a
High omega-6 PUFA diet (H6D) or a low omega-6 diet (L6D) and behavioral, electrophysiologic and lipidomic
outcomes will be measured. (Popular ketogenic diets are different as they are low omega-6 PUFA)
Aim 2: Determine the effects of H6D on DRG neuronal membrane lipid content and PLA2 isozyme(s)
expression and mechanisms for regulating nociceptor activities.
Aim 3: Determine whether switching to a L6D or to a high omega-3:Low omega 6 diet reverses the effects of a
H6D on nociception.
This project has substantial scientific and medical significance as the central hypothesis predicts that H6D will
predispose patients to chronic pain conditions and offers new targets for analgesic drug development.

## Key facts

- **NIH application ID:** 10019608
- **Project number:** 5R01NS110948-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Kenneth M Hargreaves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019608

## Citation

> US National Institutes of Health, RePORTER application 10019608, Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors (5R01NS110948-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10019608. Licensed CC0.

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